12 páginas, 6 figuras, 1 tabla.Increasing evidences suggest that nuclear pore complexes (NPCs) control different aspects of nuclear metabolism, including transcription, nuclear organization, and DNA repair. We previously established that the Nup84 complex, a major NPC building block, is part of a genetic network involved in DNA repair. Here, we show that double-strand break (DSB) appearance is linked to a shared function of the Nup84 and the Nup60/Mlp1–2 complexes. Mutants within these complexes exhibit similar genetic interactions and alteration in DNA repair processes as mutants of the SUMO-protease Ulp1. Consistently, these nucleoporins are required for maintenance of proper Ulp1 levels at NPCs and for the establishment of the appropriate sumoylation of several cellular proteins, including the DNA repair factor Yku70. Moreover, restoration of nuclear envelope-associated Ulp1 in nucleoporin mutants reestablishes proper sumoylation patterns and suppresses DSB accumulation and genetic interactions with DNA repair genes. Our results thus provide a molecular mechanism that underlies the connection between NPC and genome stability.This research was supported by a collaborative program between the Institut Curie and the Commissariat à l’Energie Atomique (PIC Paramètres Epigénétiques grant to V.D.), the Ligue Nationale contre le Cancer (Equipe Labeliseé 2006 to V.D.), the Association pour la Recherche contre le Cancer (ARC to V.D.), the Ministère de l’Education Nationale, de la Recherche et de l’Enseignement Supérieur (A.C.I. "Jeunes chercheurs" to V.D.), a Cancer Center Support Grant (NCI P30 CA-08478-41 to X.Z.), and the Ministry of Science and Education of Spain (grant SAF2003-00204 to A.A.). B.P. was supported by postdoctoral fellowships from ARC and Fondation Pour la Recherche Médicale.Peer reviewed